1-cyclopropyl-2-methoxyethanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H); LRMS (ESI) mile 250.3 [(M+H)+, calcd for C14H20NO3 250.1]. The reaction mixture was placed in an ice bath During the addition After the addition The mixture was poured into a separatory funnel extracted with CH2Cl2 (3×300 mL) The combined organic layers were washed with brine (300 mL) dried over MgSO4 filtered concentrated The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H); LRMS (ESI) mile 250.3 [(M+H)+, calcd for C14H20NO3 250.1]. The reaction mixture was placed in an ice bath During the addition After the addition The mixture was poured into a separatory funnel extracted with CH2Cl2 (3×300 mL) The combined organic layers were washed with brine (300 mL) dried over MgSO4 filtered concentrated The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H); LRMS (ESI) m/e 250.3 [(M+H)+, calcd for C14H20NO3 250.1]. The reaction mixture was placed in an ice bath During the addition After the addition The mixture was poured into a separatory funnel extracted with CH2Cl2 (3×300 mL) The combined organic layers were washed with brine (300 mL) dried over MgSO4 filtered concentrated The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes)

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H), LRMS (ESI) m/e 250.3 [(M+H)+, calcd for C14H20NO3 250.1]. The reaction mixture was placed in an ice bath During the addition After the addition The mixture was poured into a separatory funnel extracted with CH2Cl2 (3×300 mL) The combined organic layers were washed with brine (300 mL) dried over MgSO4 filtered concentrated The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H); LRMS (ESI) mile 250.3 [(M+H)+, calcd for C14H20NO3 250.1]. The reaction mixture was placed in an ice bath During the addition After the addition The mixture was poured into a separatory funnel extracted with CH2Cl2 (3×300 mL) The combined organic layers were washed with brine (300 mL) dried over MgSO4 filtered concentrated The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes)